In vitro cellular and proteome assays identify Wnt pathway and CDKN2A-regulated senescence affected in mesenchymal stem cells from mice after a chronic LD gamma irradiation in utero.
Martina SchusterGargi TewaryXuanwen BaoPrabal SubediStefanie M HauckAnn Karin OlsenDag Markus EideKlaus Rüdiger TrottSebastian GötzMichael J AtkinsonMichael RosemannPublished in: Radiation and environmental biophysics (2021)
Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC-MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells.
Keyphrases
- radiation induced
- mesenchymal stem cells
- stem cells
- bone marrow
- radiation therapy
- cell cycle
- signaling pathway
- ms ms
- pregnant women
- umbilical cord
- oxidative stress
- low dose
- dna damage
- extracellular matrix
- drug induced
- cell proliferation
- endothelial cells
- high fat diet induced
- pi k akt
- machine learning
- induced apoptosis
- circulating tumor
- endoplasmic reticulum stress
- intensive care unit
- type diabetes
- epithelial mesenchymal transition
- ischemia reperfusion injury
- deep learning
- high throughput
- respiratory failure
- mass spectrometry
- preterm infants
- high resolution
- wild type
- artificial intelligence